Superantigens have been implicated in the triggering of autoimmune rheumatic diseases through interactions with both Major Histocompatibility Complex (MHC) molecules and T cell receptors (TcR) that overcome the specificity of the normal immune response. The binding of bacterial superantigens to MHC molecules is complex, with multiple binding sites identified on the surface of the MHC molecule, which can be recognized by different bacterial superantigens. Even closely related superantigens may bind to distinct MHC surface sites. In addition, the binding of some bacterial superantigens is sensitive to the composition of peptides in the conventional MHC antigen-binding site. Thus different cellular peptides may influence the binding of superantigens to surface MHC molecules, which in turn could mean that different types of antigen-presenting cells at different inflammatory sites, may be important in modulating the ability of superantigens to activate T cells. A structural understanding of the complexity of bacterial superantigen interactions with MHC molecules may provide new insights into the ternary complexes that are formed between MHC molecules, TcRs and superantigens. The proposed research is focussed on understanding the structural differences in the binding of two closely related bacterial superantigens, the Streptococcal superantigen, SSA and the Staphylococcal superantigen, SEB. We have chosen to pursue structural studies of the SSA molecule, because it shows significant sequence homology to the SEB superantigen (approximately 60%), but binding and mutational studies with SSA indicate that it's interactions with MHC class II are different from SEB. There are two potential explanations for these observed differences. SSA may bind to a distinct MHC surface, or SSA may bind to a conformational variant of the MHC molecule that does not bind SEB, due to the influence of MHC-bound peptide. These possibilities will be addressed by the following specific aims: (1) Determine the structure of the Streptococcal pyogenes superantigen SSA; (2) Determine the peptide dependence of SSA and SEB binding to HLA-DR.; (3) Crystallize a complex between SSA and HLA-DR.
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